Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications

Table 1 MicroRNA involved in hepatocellular carcinoma and their function in the hepatocyte growth factor/c-Met axis

miRNA	Functions	Effect of miR in HGF/c-Met axis	Levels in HCC	Ref.
miR-34	Cell invasion, proliferation	Inhibits c-Met	Downregulated	[83]
miR-199	Proliferation, cell motility,	Tumor-suppressor	Downregulated	[84]
	cell invasion
miR-340	Cell invasion, cell migration	Inhibits c-Met	Downregulated	[85]
miR-126	Cell proliferation,	Inhibits c-Met	Downregulated	[86]
	cell invasion, inhibits angiogenesis
miR181-a	Cell motility and invasion	Inhibits c-Met	Upregulated	[87]
let-7 family	Represses cell proliferation, invasion, metastasis and resistance therapy	Inhibits c-Met signaling downstream	Downregulated	[88,89]
miR-148	Promotes apoptosis, suppress cell invasion	Tumor-suppressor	Downregulated	[90]
miR-1	Cell migration, cell proliferation	Tumor-suppressor	Downregulated	[91]
miR-26a	Cell proliferation, invasion, and migration	Inhibits c-Met signaling downstream	Downregulated	[92]
miR-122	Induces apoptosis	Inhibition of c-Met	Downregulated	[93]
miR-145	Cell viability, cell migration	Inhibits c-Met signaling downstream	Downregulated	[94]
miR-449	Promotes apoptosis, reduces proliferation	Decreases c-Met levels	Downregulated	[95]
miR-200	Cell migration and invasion	Decreases HGF-synthesis in fibroblasts	Upregulated	[96]
miR-101	Cell proliferation, migration and invasion	Inhibits c-Met signaling downstream	Downregulated	[97]

HCC: Hepatocellular carcinoma; HGF: Hepatocyte growth factor.

Table 2 Compounds used in clinical trials to treat hepatocellular carcinoma patients

Agent	Targets	Phase	Activity	HCC stage	Ref.
Sorafenib	Raf, MAPK, VEGFR, PDGFRβ	III	Anti-tumor	Advanced	[98]
			Anti-angiogenesis
Cabozanitinib	VEGFR2, KIT, RET, AXL	III	Anti-tumor	Advanced	[99]
Brivanib	FGFR, VEGFR	II	Anti-angiogenesis	Advanced	[100]
Foretinib	FLT1, PDGFRβ, c-Met, VEGFR-2, Tie-2	II	Anti-tumor	Advanced	[101]
	FLT4, RON, FLT3, KIT		Anti-angiogenesis
Everolimus	mTOR	III	Anti-tumor	Advanced	[102]
Cobazitinib	c-Met, VEGFR-2, RET	II	Anti-tumor	Advanced	[103]
			Anti-angiogenesis
Ramucirumab	VEGFR-2	III	Anti-angiogenesis	Advanced	[104]
MSC2156119J	c-Met	Ib/II	Anti-tumor, anti-mestastasis	Advanced	[105]
Gefitinib	EGFR, c-Met, HGF,	II	Anti-tumor	Advanced	[106]
Bevacizumab	VEGFRs	II	Anti-angiogenesis	Advanced	[107]
AZD6244	MEK1/2	Ib	Anti-tumor	Advanced	[108]
AZD4547	p-FGFR-1, p-FGFR-2	I	Anti-tumor, anti-angiogenesis	Advanced	[109]
	p-c-Met,
	p-AKT,
	p-ERK
MK2461	c-Met, Ftl-1	I	Anti-tumor	Advanced	[110]
Crizotinib	p-c-Met	Ib	Anti-angiogenesis	Advanced	[111]
	ALK
Bortezomib	Proteasome inhibitor	II	Anti-tumor	Advanced	[102]
Docetaxel	EGFR	II	Anti-tumor	Advanced
INC280	p-c-Met	II	Anti-tumor	Advanced	[111]

HCC: Hepatocellular carcinoma.

Table 3 List of compounds analyzed in laboratories that show potential anti-tumor properties against hepatocellular carcinoma

Agent	Target	Activity	Ref.
LZ8	Inhibits the expression of c-Met, ERK, AKT	Induces apoptosis	[112]
	Inhibits the phosphorylation of JNK, AKT, ERK, p-AKT
	Stabilizes p53
Damnacanthal	Inhibits the phosphorylation of c-Met	Inhibits cell proliferation and cell invasion	[113]
	Decreases MMP-2 activity
GEN-203	Inhibits the phosphorylation of c-Met	Blocks cell proliferation	[114]
JNJ38877605	Inhibits phosphorylation of c-Met	Induces apoptosis	[70]
SRI31215	Blocks pro-HGF activation	Inhibits cell proliferation	[70]
Madecassoside	Inhibits the phosphorylation of ERK1/2 and	Blocks cell proliferation	[115]
	PKC
PHA665752	Inhibits phosphorylation of c-Met and FGFR	Blocks cell proliferation	[116]
EPZ011989	Inhibits histone methylation	Blocks cell proliferation	[82]
YC-1	Inhibits the DNA synthesis	Arrests cell cycle and induce apoptosis	[117]